Engraftment of human cord blood-derived stem cells in preimmune ovine fetuses after ultrasound-guided in utero transplantation

OBJECTIVE: The fetal sheep in utero transplantation model has developed into an important tool to study the efficacy of human in utero stem cell transplantation and gene therapy because of similarities in both the scale and development of immunocompetence relative to gestational age. The aim of this study was to determine whether human stem cells can be successfully transplanted to the first-trimester ovine fetus by use of a newly developed minimally invasive technique. STUDY DESIGN: Human cord blood-derived, CD34(+)-enriched stem cells were injected into the peritoneal cavity of 45- to 60-day-old ovine fetuses by using ultrasound-guided transabdominal percutaneous needle puncture. Engraftment was determined 1 to 3 months after birth by flow cytometry with use of human-specific anti-CD45 antibodies. RESULTS: In contrast to previous studies that used surgical techniques, we observed a fetal loss rate of 24%, significantly below previous values and only marginally higher than natural loss. Successful human cell engraftment was achieved in 18% of lambs available for analysis. Engraftment levels of human cells in bone marrow of the recipient were up to 0.8% of total nucleated cells. CONCLUSION: Ultrasound-guided percutaneous transplantation of stem cells to fetal sheep in the first trimester is feasible. Although we were unable to observe a significant improvement in the level of engraftment of human cells in sheep, the decreased fetal loss rate associated with this technique allows greater use for further studies that use this model of in utero transplantation.     

In utero transplantation of autologous and allogeneic fetal liver stem cells in ovine fetuses

OBJECTIVE: The purpose of this study was to assess the feasibility of autologous stem cell transplantation in fetal sheep and to compare short-term engraftment of allogeneic and autologous fetal liver stem cells in an immunocompetent large animal model. STUDY DESIGN: Fetal liver stem cells were collected from preimmune sheep fetuses with an open or ultrasound-guided technique. After being labeled with PKH26, the cells were transplanted intraperitoneally into allogeneic and autologous fetal recipients at 48 to 64 days of gestation. Engraftment was determined by flow cytometry and real-time polymerase chain reaction 1 to 2 weeks after transplantation. RESULTS: Fetal loss rate was 29% (allogeneic transplantation) and 73% (autologous transplantation). Engraftment of donor cells was found in all fetuses, with a level of < or =4.7% in fetal liver, spleen, bone marrow, blood and thymus. Overall, there was no difference between allogeneic and autologous grafts. CONCLUSION: Autologous in utero transplantation of fetal liver stem cells in fetal sheep is feasible, but yields a high loss rate. Differences in the major histocompatibility complex between donor and recipient seems not to have a major impact on stem cell engraftment early in gestation; major histocompatibility complex-independent donor/host competition might be responsible for low engraftment in immunocompetent recipients.     

The in vivo study of myeloprotection by GST-π gene transfected human cord blood hematopoietic stem cells transplantation

To investigate the influence of GST-π gene transfer into human cord blood hematopoietie stem cells on their drug resistance against anti-turmor drugs in vivo. Methods: GST-π gene transfeetion into human cord blood CD34 ceils was carried out using a retrovirus vector PTJ-GST-π with the aid of fibronectin. Successful gene transfer was confmncd by in vitro colonyassay and RT-PCR. GST-π gene transduced human cord blood CD34 ceils were then engrafted into4-week-old to tal body irradiated NOD/Scid mice and earboplatin was intraperitoneally administered sequentially at 4 weeks interval 4 weeks after engraftment.Results:Peripheral bloed(PB) WBC wassignificantly higher in GST-π mice than control mice after 2 course of carboplatin. Retroviral GST-π expression in bone marrow hematopoietie progenitor cells of recipient mice was detected by RT-PCR16 weeks after Xenotransp/antatlon. Conclusion: The transfect/on of GST-π gene could confer, tosome extent, reslstance to cord blood stem cells against carboplatin in vivo.     

Prevention of graft rejection by donor type II CD8(+) T cells (Tc2 cells) is not sufficient to improve engraftment in fetal transplantation

OBJECTIVES: Tc2 cells, a subset of CD8(+) T cells, are able to facilitate engraftment in a murine model of postnatal allogeneic bone marrow transplantation. The purpose of this study was to evaluate whether Tc2 cells could improve engraftment in fetal transplantation. METHODS: Gestational day 13 C57BL/6 (H-2(b)) fetal mice were used as recipients, adult B6D2F(1) mice (C57BL/6 x DBA/2, H-2(b/d)) as donors, and splenocytes from B6C3F(1) (C57BL/6 x C3H/He, H-2(b/k)) mice were used as stimulators in cultures used to generate the Tc2 cells from B6D2F(1) mice. Peripheral blood chimerism was examined monthly for 3 months. Thereafter, recipients were sacrificed to evaluate the levels of peritoneal, splenic and bone marrow chimerism. The T-cell responses of recipient splenocytes to cells of host origin were measured as a proliferative response in mixed lymphocyte cultures. RESULTS: Low levels of peripheral blood cell chimerism (<0.3%) were observed at 1 month of age, which declined further by 3 months of age. The levels of donor cells in the spleen, bone marrow and peritoneal cavity were usually not more than 0.05%. The peritoneal cavity tended to have higher levels of donor cells with 1 recipient sustaining as high as 25.03% at the age of 3 months. Higher peritoneal chimerism correlated with a lower donor-specific T-cell response. CONCLUSIONS: Transplantation of Tc2 cells was insufficient to improve bone marrow engraftment in utero, suggesting that graft rejection is not the major barrier to successful in utero transplantation. Donor cells can persist in the peritoneal cavity and might play an important role in inducing immune tolerance in fetuses.     

大鼠胚胎卵黄囊内和腹腔内人脐血造血干细胞移植的比较

目的:探讨人脐血造血干细胞宫内移植的更好途径。方法:将人脐血单个核细胞注入大鼠胚胎的卵黄囊及胎鼠腹腔内,并设阴性及空白对照组,观察手术并发症及妊娠结局,待出生后1个月及2个月,分别用流式细胞仪和免疫组化检测移植情况。结果:胎鼠腹腔途径组的手术并发症发生率、胎鼠丢失率显著高于卵黄囊途径组(P<0.001,P<0.05)。出生后实验组仔鼠外周血中检测到逐渐增加的人CD3细胞,卵黄囊组的增殖量高于腹腔途径组(P<0.05)。卵黄囊组的种植率为89.7％,腹腔组的种植率为64.0％,二者比较有显著性差异(P<0.05)。出生后2个月在仔鼠的肝、脾及胸腺组织中均检测到人CD3、CD20及CD34~+阳性细胞,卵黄囊组的表达量明显高于腹腔组(P<0.001)。结论:大鼠胚胎的卵黄囊途径是人脐血造血干细胞进行宫内移植的一条较好途径。     

In utero hematopoietic stem cell transplantation: a caprine model for prenatal therapy in inherited metabolic diseases

OBJECTIVES: We explored the feasibility and efficacy of in utero hematopoietic stem cell transplantation in the caprine animal model system with the objectives of determining procedures for transplantation and establishing methods for detecting engraftment. METHODS: Male fetal liver hematopoietic stem cells were injected into female fetuses during the immunotolerant period, using either hysterotomy or ultrasound-guided injections. RESULTS: The rate of fetal death was much lower for the ultrasound-guided injections. Donor cells were observed in the peritoneal fluid of 4 fetuses 3 days after injection, but no donor cells were detected in tissues at longer time periods. CONCLUSIONS: Ultrasound-guided injection of hematopoietic stem cells into the abdomen of a developing fetus is safe and feasible. The parameters required for successful engraftment have not yet been identified.     

Association of stress during delivery with increased numbers of nucleated cells and hematopoietic progenitor cells in umbilical cord blood

OBJECTIVE: Umbilical cord blood can be used as a source of bone marrow repopulating cells for allogeneic stem cell transplantation. Large variations in the frequencies of white blood cells and hematopoietic progenitor cells have been found for umbilical cord blood. These variations may be due in part to specific circumstances during labor and delivery. STUDY DESIGN: In this study we analyzed the relationship between stress factors occurring during parturition and the frequencies of nucleated cells, leukocyte subsets, CD34(+) cells, and hematopoietic progenitor cells, as determined in semisolid medium cultures of umbilical cord blood. RESULTS: We observed that a prolonged first stage of labor resulted in increases in the numbers of nucleated cells, granulocytes, CD34(+) cells, and hematopoietic progenitor cells in umbilical cord blood. Evaluation of parameters that indicate stress of the infant during delivery demonstrated higher numbers of nucleated cells, granulocytes, CD34(+) cells, and hematopoietic progenitor cells in umbilical cord blood from children with lower venous pH. CONCLUSION: Longer duration stress during delivery increased the numbers of nucleated cells, granulocytes, CD34(+) cells, and hematopoietic progenitor cells, possibly by causing mobilization of various cell populations by endogenous cytokines. As long as umbilical cord blood harvesting does not interfere with the delivery, umbilical cord blood collected after stressful deliveries may provide optimal units for hematopoietic stem cell transplantation.     

Cord blood for allogeneic and autologous banking

Allogeneic transplantations of haematopoietic stem cells derived from cord blood have become a clinical routine. Applications are successful in malignant and non-malignant diseases, with high engraftment capacities and, compared to bone marrow stem cell transplantations, less strict human leucocyte antigen-match criteria. A major concern in using haematopoietic stem cells from cord blood is the relatively low number of stem cells that can be retrieved; however, recent research focuses on using several cord blood transplants as tandem transplants or increasing the number of progenitors by in vitro expansion strategies. In contrast to these running applications in allogeneic stem cell transplantation, autologous stem cell transplantations so far are very rare, and future indications, such as in regenerative medicine, are still experimental.     

In utero hematopoietic stem cell transplantation with haploidentical donor adult bone marrow in a canine model

OBJECTIVE: Chimerism can be achieved in a canine model of in utero bone marrow transplantation with > or =1 x 10(8) CD34(+) haploidentical donor cells per kilogram without graft-versus-host disease. STUDY DESIGN: In utero bone marrow transplantation was performed by ultrasound-guided intraperitoneal infusion in 30- to 41-day-old canines with CD34(+) selected cells from paternal bone marrow at doses of 1.3 x 10(8) to 2.5 x 10(10) CD34(+) cells/kg. A method for marking control littermates was developed with intraperitoneal ethiodol. Postnatal studies included histologic, fluorescent in situ hybridization canine Y probe, and polymerase chain reaction-based chimerism analyses. RESULTS: Term survival was 86% to 100% for transplantations > or =34 days versus 14% and 43% at 30 and 31 days. Microchimerism (<1%) was demonstrated in tissues from 4 informative litters that included thymus, liver, skin, spleen, and intestine. Neither gestational age nor donor CD34 cell dosage altered the level of engraftment in these experiments. There was no evidence of graft-versus-host disease. CONCLUSION: In utero bone marrow transplantation in a canine model achieves microchimerism with high CD34(+) cell doses.     

Use of T-cell antibodies for donor dosaging in a canine model of in utero hematopoietic stem cell transplantation

AIM: Microchimerism following canine in utero hematopoietic stem cell transplantation (IUHSCT) development of T-cell dosing regimens. OBJECTIVE: To investigate the use of anti-T-cell antibodies for cell dosing of the donor graft in a canine model of IUHSCT. STUDY DESIGN: Canine IUHSCT was performed by ultrasound-guided intraperitoneal injection in days 35-38 of fetal canines with CD34(+) cells at doses of 4.5 x 10(8) to 1.3 x 10(9) cells/kg and T cells (CD3(+) CD5(+)) at doses of 8 x 10(6) to 8.8 x 10(8) cells/kg. Postnatal studies included tissue histology and polymerase chain reaction-based chimerism analysis. RESULTS: Term survival was 86-100%. Microchimerism (0-2%) was detected in five of eight recipients in multiple tissues. Histopathology revealed no evidence of graft-versus-host disease (GVHD). CONCLUSION: Canine IUHSCT is a useful model to investigate the role of donor T cells in engraftment and GVHD. IUHSCT at early gestational ages with high doses of donor T cells in the graft yields microchimerism in multiple tissues without GVHD.     

Which stem cells should be used for transplantation?

In view of the ever-increasing demand for human stem cells for transplantation, we initiated in vitro and in vivo studies of human fetal bone marrow stem/progenitor cells derived from lost pregnancies at 16-20 weeks. Utilizing non-human primates as models, we demonstrated that fetal tissue has distinctive biological and therapeutic properties that are optimal for transplantation. Subsequently, we tested and compared the phenotypic and functional characteristics of fetal bone marrow (FBM), adult bone marrow (ABM), and cord blood (CB) and peripheral blood (PB) sources of the most primitive stem/progenitor cells. A striking ontogenic difference in the proportion of CD34+ cells in FBM, ABM, PB and CB was observed (24.6 vs. 2.1 vs. 0.5 vs. 2%). The clonogenic potential, as measured by the CFU-c assay, was also higher in FBM when compared with ABM, PB and CB (202.5 vs. 73.5 vs. 40.8 vs. 65.5 colonies/10(5 )cells). Moreover, there was a significant decrease in proliferative responsiveness in the mixed lymphocyte reaction (MLR) assay of FBM and CB as compared to ABM and PB. The cytokinetic profiles of the cells from the four sources were also analyzed. This study revealed that both FBM and ABM had a higher proportion of S-phase (21.7 and 11.5%, respectively), compared to PB and CB cells (1.2 and 2.8%, respectively). FBM and ABM also showed a higher proportion of cells in the G(2)-M phase (6.4 and 2.6%, respectively) compared with PB and CB (1.7 and 1.2%, respectively). These data show that FBM has the highest number of proliferating cells. We have also investigated the ontogenic differences in stromal cells derived from FBM, ABM and CB, with a special focus on the expression of selected cytokines, such as CSF, GM-CSF, G-CSF, M-CSF, IL-3, IL-6, IL-10 and IL-11. FBM showed the highest levels of expression of CSF, IL-6 and IL-11 when compared to the other sources. These cytokines may have an important role in engraftment and homing of stem cells. The levels of expression of the other cytokines were similar in all sources of stromal cells, with the exception of G-CSF, which was not detected in CB. Moreover, the number of colonies FBM and ABM cells was higher when inoculated with fetal stromal cells. These results suggested an important regulatory role of cytokines in ontogeny of hematopoiesis. In summary, the foregoing observations indicate that each source of hematopoietic and stromal cells has different intrinsic properties, closely correlated with ontogenetic age, which is a vital determinant for phenotypic characteristics, lineage commitments, immunogenicity as well as proliferative potentials. Our data clearly indicate that FBM is the best source of stem cells for engraftment and therapeutic reconstitution due to its very high proliferative capacity, low immunogenicity and highest number of primitive stem/progenitor cells. It should also be stressed that FBM stem cells retrieved at their optimal stage of hematopoiesis (16-20 weeks) may be the cells of choice for both therapeutic cellular reconstitution and gene targeting.     

Tissue-specific engraftment after in utero transplantation of allogeneic mesenchymal stem cells into sheep fetuses

OBJECTIVE: Mesenchymal stem cells (MSC) have multiorgan differentiation capacity, providing the potential for prenatal treatment of genetic disorders. We address the question if in utero transplantation of MSC results in short-term organ-specific engraftment in the fetal sheep. STUDY DESIGN: Sheep fetal liver-derived MSC selected by adherence culture (passage 1) were transplantated into the fetal peritoneal cavity with ultrasound-guidance (mean gestational age, 59 days). After 14 days recipient fetuses were analyzed by fluorescence-activated cell sorting (FACS), real-time polymerase chain reaction (PCR), and immunohistochemistry. RESULTS: Fetuses (n = 11) were transplanted with 7.7 x 10(6) MSCs (mean). All surviving fetuses (n = 5) showed engraftment with mean levels of 3.2% (lung), 0.8% (spleen), 0.6% (liver, brain), 0.4% (bone marrow), 0.1% (blood, thymus), and <0.1% (kidneys) by flow cytometry. Immunohistochemistry showed organ-specific distribution. CONCLUSION: In utero transplantation of allogeneic MSC results in low level, multiorgan engraftment at 14 days post transplant. This supports the potential of in utero MSC transplantation for the treatment of nonhematopoietic genetic disorders of the fetus.     

Developmental changes in adhesion molecule expressions in umbilical cord blood CD34 hematopoietic progenitor and stem cells

OBJECTIVE: The purpose of this study was to determine whether expressions of the cell adhesion molecules LFA-1 (CD11a), VLA-4 (CD49d), and L -selectin (CD62L ) on CD34(+) stem and progenitor cells in umbilical cord blood change during gestation. STUDY DESIGN: In a prospective observational study 3-color fluorescence-activated cell sorting was used to assess the levels of expression of CD11a, CD49d, and CD62L on CD34(+) cells in fresh cord blood samples collected at delivery between 22 and 42 weeks' gestation. RESULTS: The relative number of CD34(+) cells decreased as gestational age increased (r = -0.71; P<.001). Conversely, we found significant increases in cell adhesion molecule expression by CD34(+) cells during gestation (LFA-1, r = 0.47; P =.001; VLA-4, r = 0.33, P =.031; L -selectin, r = 0.61; P<.001). Comparisons between grouped samples from early preterm (22-32 weeks' gestation), late preterm (33-37 weeks' gestation), and term (38-42 weeks' gestation) infants confirmed this correlation and revealed that the major increases occurred between early and late preterm gestation. CONCLUSION: These results suggest a role for cell adhesion molecule expression in the process of migration and homing of circulating stem cells to the fetal bone marrow toward the end of pregnancy. The findings may have implications for the use of preterm cord blood for hematopoietic stem cell transplantation and also for prenatal gene therapy.     

Umbilical Cord Blood Banking: A Current Perspective

Placental and umbilical cord blood (UCB) is becoming an important source of haematopoietic stem cells for use in clinical transplantation. Now that over 500 cord blood transplantations have occurred worldwide, clinical experience is demonstrating some distinct advantages to these cells over the traditional bone marrow sources. These advantages include distinctive proliferative capacities which favour engraftment. Umbilical cord blood use is associated with a reduced incidence and severity of Graft versus Host disease, and recipients may tolerate a greater number of HLA mismatches than with bone marrow source stem cells.Umbilical cord blood stem cells have also opened up areas of active laboratory and clinical investigation that could ultimately result in further therapeutic options. The most exciting areas are those of ex vivo cell expansion and a variety of applications involving stem cells as vehicles for potential gene therapy.Cord blood banks can retain these separated stem and progenitor cells to provide an additional, immediately accessible resource to a bone marrow registry. In Europe, NETCORD links three cord blood banks to its bone marrow donor worldwide registry, and in the United States, three cord blood banks are also linked to a central bone transplant registry. In Canada, the Bone Marrow Transplant Registry, administered by The Canadian Red Cross, is investigating options for a similar structure. However, there is no established funding at this time for a Canadian system of this scale.     

Obstetric predictors of placental/umbilical cord blood volume for transplantation

OBJECTIVE: Umbilical cord blood is an effective alternative to bone marrow as a source of hematopoietic stem cells in transplantation. However, the amount of donor blood and the cell content that are collected may be insufficient for engraftment in some adult recipients. This study identifies obstetric factors that affect retrievable placental cord blood volume. STUDY DESIGN: A retrospective analysis of factors that were obtained by direct observation or medical record review that were related to harvested cord blood volume was conducted; the analysis involved 9205 deliveries from mothers who donated placental cord blood through the obstetric services of two New York City hospitals between 1993 and 1999. RESULTS: Obstetric factors that influenced significantly the total volume of blood that was collected were route of delivery, induction of labor, presence of a nuchal cord, infant birth weight, multiple births, placental weight, and duration of labor. The length of the umbilical cord from the venipuncture site and the length of time to cord blood collection also affected the volume that was retrieved. Maternal ethnicity was associated with cord blood yield; Caucasian mothers provided larger quantities than either African American or Asian mothers. CONCLUSION: Our results confirm that the volume of residual placental cord blood that is collected for hematopoietic stem cell transplantation is influenced by several factors, the presence of which predict the likelihood of an adequate collection. Collected volumes can be improved when a longer length of the cord is left with the placenta and when there is a shorter time between the delivery of the placenta and the collection.     

Normal development of human fetal hematopoiesis between eight and seventeen weeks' gestation

OBJECTIVE: The aim of this study was to compare the hematologic compositions of fetal blood and liver and to phenotypically quantify the hematopoietic stem and progenitor cells during early human gestation. STUDY DESIGN: Fifty fetal blood samples and 50 fetal livers were collected at 10 to 17 weeks' gestation and 8 to 17 weeks' gestation, respectively. Investigations included fetal blood cell counts, determinations of red blood cell index values, and flow cytometric analyses of mononuclear cells. RESULTS: Fetal red blood cell, white blood cell, and platelet counts all increased with gestation, reflecting hematologic development. The proportion of normoblasts decreased dramatically with gestation. Individual mature red blood cells were larger and contained more hemoglobin during early gestation. Circulating and hepatic T lymphocytes increased in number shortly before the 13th week of gestation, which reflected thymic maturation. As a proportion fetal liver contained fewer T lymphocytes than did fetal blood (2.5% vs 18.6%; P =.003) but more CD34(+) hematopoietic stem and progenitor cells (17.5% vs 4.3%; P =. 004). As a proportion, fetal liver contained more of the primitive CD34(+) and CD38(-) hematopoietic stem and progenitor cells than did fetal blood (32% vs 17%; P =.04). CONCLUSION: Both fetal blood and liver provide a rich source of hematopoietic stem and progenitor cells. Fetal liver provides a richer source of more primitive hematopoietic stem and progenitor cells than does fetal blood. For stem cell transplantation we suggest that fetal livers be collected before the 13th week of gestation, because T lymphocytes are present in much greater numbers in the fetal liver after this stage of gestation. Further, we suggest that in utero stem cell transplantations in fetuses with normal immune development should be performed before the 13th week of gestation.     

Ultrasound-guided stem cell sampling from the early ovine fetus for prenatal ex vivo gene therapy

OBJECTIVE: Prenatal ex vivo gene therapy might be an effective and safe strategy with which to treat severe genetic disorders in utero. For this purpose, autologous fetal stem cells must be collected before the second trimester, transfected in vitro, and transplanted back to the fetus. The aim of this study was to determine whether stem cells can be sampled from the first trimester fetal liver in ongoing gestation. STUDY DESIGN: Fetal liver stem cell sampling was performed in 21 ovine fetuses. Pregnant ewes at 57 +/- 2 gestational days were generally anesthesized. A 20-gauge needle was inserted transcutaneously into the fetal liver under ultrasound guidance. Fetal liver cells were sampled by suction. The numbers of nucleated cells and progenitor/stem cells were determined. RESULTS: All 21 fetuses showed normal heart rate 5 minutes after the procedure. A mean (+/-SEM) of 2.07 +/- 0.5 x 10(7) nucleated cells and 172 +/- 53 colony-forming units per 10(5) cells (hematopoietic progenitors/stem cells) were collected. Fetal loss rate at term was 7 of 21 fetuses (33%). CONCLUSION: This study shows that fetal liver cells can be collected in the early fetus with an ultrasound-guided technique. The number of fetal liver cells that are collectable is large enough for autologous transplantation and engraftment of genetically engineered (transfected) stem cells.     

Mixed lymphocyte culture of human fetal liver cells

OBJECTIVE: In order to study the immunological function of the human fetus in the first and second trimesters, mixed lymphocyte culture (MLC) of fetal liver and thymic cells was performed. MLC is a functional test to determine human lymphocyte antigen-D incompatibilities. METHODS: Human fetal liver and thymic tissue was obtained from abortions in gestational weeks 7-17.5. Forty-seven fetuses were studied with one-way MLC. The cells were stimulated by adding irradiated fetal liver cells, adult bone marrow and peripheral blood lymphocytes. The activity was measured as DNA incorporation of radiolabeled thymidine. RESULTS: The results indicate that the human fetus is competent to react as early as 11-12 weeks of gestation and in some cases even earlier. In very immature fetal livers (< 8 weeks), the MLC seems to be inhibited. CONCLUSIONS: Our data suggest that the human fetus can react against foreign transplantation antigens earlier than previous papers have claimed. The onset of reactivity seems to differ considerably among fetuses. The present findings may explain some of the limited success of in utero transplantations of hematopoietic stem cells in human fetuses of normal immunological status.     

Fetal stem cells

Fetal stem cells can be isolated from fetal blood and bone marrow as well as from other fetal tissues, including liver and kidney. Fetal blood is a rich source of haemopoietic stem cells (HSC), which proliferate more rapidly than those in cord blood or adult bone marrow. First trimester fetal blood also contains a population of non-haemopoietic mesenchymal stem cells (MSC), which support haemopoiesis and can differentiate along multiple lineages. In terms of eventual downstream application, both fetal HSC and MSC have advantages over their adult counterparts, including better intrinsic homing and engraftment, greater multipotentiality and lower immunogenicity. Fetal stem cells are less ethically contentious than embryonic stem cells and their differentiation potential appears greater than adult stem cells. Fetal stem cells represent powerful tools for exploring many aspects of cell biology and hold considerable promise as therapeutic tools for cell transplantation and ex vivo gene therapy.     

Fetal hematopoietic stem cell transplantation

In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising approach for the treatment of a potentially large number of fetuses affected by congenital hematologic disorders. With technical and molecular advances in prenatal diagnosis, the majority of these diseases can now be diagnosed early in gestation, allowing consideration of prenatal treatment. In addition, technical advances in fetal imaging and intervention make it possible to perform the transplants with relatively minimal risk. It, therefore, stands to reason that there is increasing interest in performing in utero hematopoietic stem cell transplantation at many fetal treatment centers. Although the approach remains experimentally promising, expansion of clinical application will depend on improved understanding of the biological barriers to engraftment in the fetus as well as the development of effective clinical strategies based on the hematopoietic biology of individual disorders. This article presents the current status of this emerging therapeutic approach.